Mechanism Underlying the Effects of Estrogen Deficiency on Otoconia.

Otoconia-related vertigo and balance deficits, particularly benign paroxysmal positional vertigo (BPPV), are common. Our recent studies in humans show that, while BPPV prevalence greatly increases with age in both genders, peri-menopausal women are especially susceptible. In the present study, we show that bilateral ovariectomized (OVX) mice have significant balance behavioral deficits, and that estrogen deficiency compromises otoconia maintenance and anchoring by reducing the expression of otoconial component and anchoring proteins. There is ectopic debris formation in the ampulla under estrogen deficiency due to aberrant matrix protein expression. Furthermore, phytoestrogen is effective in rescuing the otoconia abnormalities. By comparing the expression levels of known estrogen receptor (Esr) subtypes, and by examining the otoconia phenotypes of null mice for selected receptors, we postulate that Esr2 may be critical in mediating the effects of estrogen in otoconia maintenance.

A null mutation of mouse Kcna10 causes significant vestibular and mild hearing dysfunction.

KCNA10 is a voltage gated potassium channel that is expressed in the inner ear. The localization and function of KCNA10 was studied in a mutant mouse, B6-Kcna10(TM45), in which the single protein coding exon of Kcna10 was replaced with a beta-galactosidase reporter cassette. Under the regulatory control of the endogenous Kcna10 promoter and enhancers, beta-galactosidase was expressed in hair cells of the vestibular organs and the organ of Corti. KCNA10 expression develops in opposite tonotopic gradients in the inner and outer hair cells. Kcna10(TM45) homozygotes display only a mild elevation in pure tone hearing thresholds as measured by auditory brainstem response (ABR), while heterozygotes are normal. However, Kcna10(TM45) homozygotes have absent vestibular evoked potentials (VsEPs) or elevated VsEP thresholds with prolonged peak latencies, indicating significant vestibular dysfunction despite the lack of any overt imbalance behaviors. Our results suggest that Kcna10 is expressed primarily in hair cells of the inner ear, with little evidence of expression in other organs. The Kcna10(TM45) targeted allele may be a model of human nonsyndromic vestibulopathy.

Real-ear output measures of ear level fluency devices.

OBJECTIVE: The purpose of this study was to measure real-ear aided and saturated responses of SpeechEasy™ devices and compare responses while devices delivered altered auditory feedback (AAF) and non-altered feedback (NAF). DESIGN: A repeated measures quasi-experimental design was employed. STUDY SAMPLE: Ten people fitted with completely-in-the-canal or open fit behind-the-ear devices participated. Probe microphone measures were obtained with speech, and 17 chirp stimuli presented at 75 dB and 85 dB SPL, respectively. Measurements were compared with devices delivering AAF (i.e. delayed and frequency shifted) versus NAF. RESULTS: Maximum outputs were approximately 100-105 dB SPL in the 2000-4000 Hz range. Statistically significant differences in device SPL output as a function of device setting (AAF vs. NAF) were found for seven chirp stimuli (p <.05) when levels were sampled at points that were not temporally aligned with the output chirps but not for speech stimulus (p = .17). Device output varied across individuals and with open fit devices dominated by ear canal resonance effects. CONCLUSIONS: Real-ear aided responses were equivalent with speech input when devices delivered AAF and NAF. Real-ear saturated responses were not, however, comparable between AAF and NAF settings and may be underestimated if AAF delay is not accounted for.

Hair bundle defects and loss of function in the vestibular end organs of mice lacking the receptor-like inositol lipid phosphatase PTPRQ.

Recent studies have shown that mutations in PTPRQ, a gene encoding a receptor-like inositol lipid phosphatase, cause recessive, nonsyndromic, hereditary hearing loss with associated vestibular dysfunction. Although null mutations in Ptprq cause the loss of high-frequency auditory hair cells and deafness in mice, a loss of vestibular hair cells and overt behavioral defects characteristic of vestibular dysfunction have not been described. Hair bundle structure and vestibular function were therefore examined in Ptprq mutant mice. Between postnatal days 5 and 16, hair bundles in the extrastriolar regions of the utricle in Ptprq(-/-) mice become significantly longer than those in heterozygous controls. This increase in length (up to 50%) is accompanied by the loss and fusion of stereocilia. Loss and fusion of stereocilia also occurs in the striolar region of the utricle in Ptprq(-/-) mice, but is not accompanied by hair bundle elongation. These abnormalities persist until 12 months of age but are not accompanied by significant hair cell loss. Hair bundle defects are also observed in the saccule and ampullae of Ptprq(-/-) mice. At ∼3 months of age, vestibular evoked potentials were absent from the majority (12 of 15) of Ptprq(-/-) mice examined, and could only be detected at high stimulus levels in the other 3 mutants. Subtle but distinct defects in swimming behavior were detected in most (seven of eight) mutants tested. The results reveal a distinct phenotype in the vestibular system of Ptprq(-/-) mice and suggest similar hair bundle defects may underlie the vestibular dysfunction reported in humans with mutations in PTPRQ.

Otoferlin is critical for a highly sensitive and linear calcium-dependent exocytosis at vestibular hair cell ribbon synapses.

Otoferlin, a C2-domain-containing Ca(2+) binding protein, is required for synaptic exocytosis in auditory hair cells. However, its exact role remains essentially unknown. Intriguingly enough, no balance defect has been observed in otoferlin-deficient (Otof(-/-)) mice. Here, we show that the vestibular nerve compound action potentials evoked during transient linear acceleration ramps in Otof(-/-) mice display higher threshold, lower amplitude, and increased latency compared with wild-type mice. Using patch-clamp capacitance measurement in intact utricles, we show that type I and type II hair cells display a remarkable linear transfer function between Ca(2+) entry, flowing through voltage-activated Ca(2+) channels, and exocytosis. This linear Ca(2+) dependence was observed when changing the Ca(2+) channel open probability or the Ca(2+) flux per channel during various test potentials. In Otof(-/-) hair cells, exocytosis displays slower kinetics, reduced Ca(2+) sensitivity, and nonlinear Ca(2+) dependence, despite morphologically normal synapses and normal Ca(2+) currents. We conclude that otoferlin is essential for a high-affinity Ca(2+) sensor function that allows efficient and linear encoding of low-intensity stimuli at the vestibular hair cell synapse.

Test-retest reliability of low-level evoked distortion product otoacoustic emissions.

PURPOSE: The purpose of this study was to examine test-retest reliability of low-level evoked distortion product otoacoustic emissions (DPOAEs) as a function of L(1), L(2) level; f(2) frequency; and test condition. A predictive relationship between these variables and the presence/absence of DPOAE responses was also examined. METHOD: Sixteen normal-hearing young adults participated. DPOAEs were evoked to 12 tones with f(2) frequencies ranging from 1500 Hz to 7546 Hz at 4 L(2) levels between 45 dB SPL and 30 dB SPL. Four test conditions were employed: (a) initial test, (b) retest without probe removal, (c) retest with probe reinsertion, and (d) retest with probe reinsertion by a second tester. RESULTS: L(1), L(2) level and f(2) frequency were statistically significant (p < .0001) predictors of a DPOAE response (i.e., the presence of a DPOAE response was more likely to be observed at higher L(1), L(2) levels and lower f(2) frequencies regardless of test condition). DPOAE levels were significantly affected by L(1), L(2) level and f(2) frequency (p < .0001) but not by test condition. Intra- and intertester test-retest differences were not significantly different. CONCLUSIONS: The prevalence of missing responses coupled with large intersubject variability and intrasubject test-retest variability are a detriment to the clinical utility of DPOAEs evoked with low-level stimuli.

Neurovestibular modulation of circadian and homeostatic regulation: vestibulohypothalamic connection?

Chronic exposure to increased force environments (+G) has pronounced effects on the circadian and homeostatic regulation of body temperature (T(b)), ambulatory activity (Act), heart rate, feeding, and adiposity. By using the Brn 3.1 knockout mouse, which lacks vestibular hair cells, we recently described a major role of the vestibular system in mediating some of these adaptive responses. The present study used the C57BL6JEi-het mouse strain (het), which lacks macular otoconia, to elucidate the contribution of specific vestibular receptors. In this study, eight het and eight WT mice were exposed to 2G for 8 weeks by means of chronic centrifugation. In addition, eight het and eight WT mice were maintained as 1G controls in similar conditions. Upon 2G exposure, the WT exhibited a decrease in T(b) and an attenuated T(b) circadian rhythm. Act means and rhythms also were attenuated. Body mass and food intake were significantly lower than the 1G controls. After 8 weeks, percent body fat was significantly lower in the WT mice (P < 0.0001). In contrast, the het mice did not exhibit a decrease in mean T(b) and only a slight decrease in T(b) circadian amplitude. het Act levels were attenuated similarly to the WT mice. Body mass and food intake were only slightly attenuated in the het mice, and percent body fat, after 8 weeks, was not different in the 2G het group. These results link the vestibular macular receptors with specific alterations in homeostatic and circadian regulation.